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New York,
New York10021

Purpose:

The investigator's hypothesis is that active injectors will show a partial reduction in
markers of immune activation with HCV therapy whereas non-injectors will show a more
significant reduction in these markers, and will exhibit levels of immune activation that
approach that seen in similarly studied healthy volunteers.This is based on observations that
this group of investigators have made. They have shown that individuals who inject drugs have
high level of immune activation in blood and tissue. Immune activation or chronic
inflammation has been associated with accelerated aging, cardiovascular, renal and liver
disease as well as CNS dysfunction. It remains unclear whether increased levels of immune
activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C,
chronic opiate use, or perhaps combinations of all 3. To understand the potential
contribution of infection with Hepatitis C the investigators will compare levels of immune
activation pre- and post treatment with an all oral, one pill once daily, interferon sparing
treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting
with drugs and the other free of injection for at least 4 months. Immune activation
comparisons will also include non-injecting healthy volunteers.

Study summary:

This group of multidisciplinary investigators has discovered increased levels of immune
activation among HIV-1-uninfected active injection drug users (IDUs) when compared to non-IDU
controls . The vast majority (80%) are also infected with HCV.
Active injectors have high levels of immune activation as measured by sCD14, CD8
co-expression of CD38 and HLA-DR, as well as Type 1 cytokines.
Within months of ceasing injecting, there are observable decreases in some parameters however
in general they remain elevated when compared to non-injecting healthy volunteers.
As approximately 80% of these subjects are HCV infected and viremic, these results are
confounded as to the cause of the observed increased levels of markers of immune activation-
active injection or chronic Hepatitis C. Until recently HCV treatment required the use of IFN
which has immunomodulatory activity which would cause perturbations in the markers of immune
activation. However the development of direct acting agents (DAA) to treat HCV has
revolutionized therapy. In this trial the investigators will employ the once daily FDC
formulation of sofosbuvir and ledipasvir to assess changes in markers of immune activation
during therapy.
There have been multiple clinical trials of FDC LDV-SOF in patients with Genotype 1 HCV. When
taken once daily for 12 weeks, sustained virologic response rates have been very high with
response rates nearing 99% in most studies with a 12-week course of therapy.
Common adverse events associated with FDC LDV-SOF in ION-1 include fatigue (21%), headache
(25%), nausea (11%), insomnia (8%), asthenia (7%), diarrhea (11%), rash (7%), irritibility
(7%), cough (3%), and pruritis (5%).
Ledipasvir undergoes minimal metabolism and expectations are that this medication will have
few clinically significant drug-drug interactions. In general, sofosbuvir is considered to
have relatively few clinically significant drug-drug interactions, but coadministration of
sofosbuvir with the following medications is not recommended because these medications may
significantly lower sofosbuvir levels:
Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin
Antimycobacterials: rifabutin, rifampin, rifapentine Herbal Supplements: St. John's wort HIV
Protease Inhibitors: tipranavir-ritonavir Antiarrhythmic Drugs : amiodarone (Cordarone®,
Nexterone®, Pacerone®)
Participants will be provided with a 12-week course of FDC LDV-SOF which will provide a near
99% likelihood of a SVR in participants who are adherent to therapy with low likelihood of
significant adverse events and drug-drug interactions.
In treating HCV effectively the investigators will measure changes in immune activation and
gene expression that accompany HCV treatment.